The present invention relates generally to the field of conducting polymers and specifically to an ester-linked polymer containing pyrrole and thiophene units that is biodegradable.
Electrical charges and electrical fields have beneficial healing effects on various tissues, including bone, cartilage, skin and connective tissue, cranial and spinal nerves, and peripheral nerves. Other studies have suggested that applied electrical fields can lead to regression of tumors. Thus, potential clinical applications of electrical stimulation range from the enhancement of healing of bone fractures and damaged cartilage to the treatment of ulcers and pressure sores on diabetic and bed-ridden patients. Applications in the nervous system include the treatment of spinal cord injury, and plastic and reconstructive surgery, in which peripheral nerve grafts are currently required.
More importantly, biomaterials possessing electrical properties offer the key advantage of being able to locally stimulate a desired tissue. Several electroactive polymers exist including piezoelectric (e.g., polyvinylidene fluoride) and electrically conducting materials (e.g., polypyrrole (PP), and polythiophene). Since piezoelectric materials depend on small mechanical deformations to produce transient surface charges, the level and duration of focused stimulation cannot be controlled. In contrast, electrically conducting polymers readily permit external control over both the level and duration of stimulation. Thus strategies designed to enhance the regeneration of a responsive cell might employ electrically conducting polymers.
There is currently no effective treatment for damage to central nervous system (CNS) nerves or for absolute tissue regeneration, although drugs can reduce swelling and damage to the tissue such as the spinal cord. In contrast to spinal cord injury, there exist therapies, although not optimal, for the treatment of damaged peripheral nerves. Current clinical treatments for peripheral nerve injury are surgical end-to-end anastomoses and autologous nerve grafts. Surgical end-to-end repair involves the direct reconnection of individual nerve fascicles and is useful only if nerve ends are directly adjacent, as tension in the nerve cable prohibits regeneration. To repair a nerve over a gap, autologous nerve grafts are used to physically guide the regenerating axons and to prevent the infiltration of occluding connective tissue. Unfortunately, there are several disadvantages to such nerve grafts, including loss of function at the donor site, mismatch of nerve cable dimensions between the donor graft and recipient nerve, and the need for multiple surgeries.
In an effort to surpass limitations of current treatments for peripheral nerve damage and to overcome the barriers to CNS regeneration, researchers are investigating the use of nerve guidance channels (NGCs) to bridge the gap between damaged nerve ends in the peripheral nervous system (PNS) and CNS. NGCs help direct axons sprouting off the regenerating (proximal) nerve end, provide a conduit for diffusion of neurotrophic factors secreted by the damaged nerve ends, and minimize infiltrating fibrous tissue that may impede regeneration. Several strategies to engineer an ideal NGC have been proposed, including the use of natural collagen matrices and the use of synthetic biomaterials such as polylactic acid. Synthetic materials, as opposed to natural counterparts, can be designed to incorporate a wide variety of well-defined features that enhance nerve regeneration. For example, growth factor release, permeability, and electrical conductivity have been shown to promote the regeneration of nerves. In addition, properties such as biodegradation, mechanical strength, and ease of material processing can be readily addressed using synthetic constructions. Thus, materials possessing these qualities will be most attractive for use in tissue engineering therapeutics in general, and specifically for a nerve graft alternative.
As already mentioned, electrical charges play an important role in stimulating either the proliferation or differentiation of various cell types such as osteoblasts (bone cells) and nerves. To take advantage of the beneficial effect of electrical stimulation on tissue regeneration, such as nerve, skeletal, or other living tissue, researchers have explored the utility of the piezoelectric polymer polyvinylidine-difluoride (PVDF) and poled polytetrafluoro-ethylene (PTFE). Both electroactive polymers promote enhanced neurite outgrowth in vitro and enhanced nerve regeneration in vivo. This effect has been attributed to either transient or static surface charges in the material. Synthetic scaffolds have been proposed for tissue repair and regeneration.
There remains a need, however, for biodegradable and bioactive polymers for tissue engineering that stimulate both tissue repair and regeneration. In addition, despite past research efforts in nerve regeneration, there still exists a need for a clinically attractive alternative to nerve or vein autografts.
The subject matter of the present invention includes a novel biodegradable conducting polymer for biomedical applications. The terms xe2x80x9cconducting polymerxe2x80x9d and xe2x80x9celectrically conducting polymerxe2x80x9d are used interchangeably in this application. The polymer combines mixed heteroaromatic conductive segments of pyrrole and thiophene with flexible aliphatic chains via degradable ester linkages. In addition to its utility for peripheral nerve regeneration, the polymer could also be applied to other areas of tissue engineering as well, such as spinal cord regeneration, wound healing, bone repair, and muscle tissue stimulation.
In one form, the present invention is a chemical compound having the general structure: 
where n and nxe2x80x2 are independently from 0 to 10 methylene units, and R1, R2, R3 and R4 are each independently a substituent selected from the group consisting of hydrogen, alkyl, aryl, halogen, hydroxyl, carboxyl or a salt thereof. X and Xxe2x80x2 are independently oxygen or nitrogen atoms that form ester or amido linkages, respectively; and Y and Yxe2x80x2 are independently an OH or a NH2 substituent; and Z and Zxe2x80x2 are each independently a substituent selected from the group consisting of hydrogen, alkyl, aryl, halogen, hydroxyl, carboxyl or a salt thereof.
The present invention may also be a biodegradable conducting polymer for tissue engineering using the chemical compound described above. For example, the present invention also includes the synthesis of a compound for use in the preparation of a biodegradable conducting polymer according to the SCHEME: 
In another form, the present invention is a biodegradable conducting polymer prepared by the method described above. The present invention is a method for preparing a conducting polymer by reacting compound 7 (SCHEME 1) with a diacid chloride to form compound 8 (SCHEME 1).
The present invention also includes a method for the synthesis of a biodegradable conducting polymer according to SCHEME 1 and the biodegradable electrically conducting polymer produced by the method.
The present invention may also be a biodegradable conducting polymer with a repeating unit of the following structure: 
wherein n=1 to 10.
In yet another form, the present invention is a method for stimulating cell response by contacting a conducting polymer with a repeating unit of the formula: 
where n=1 to 10 with one or more cells and applying an electrical current of sufficient power to stimulate but not harm the cells.